Apparatus and method of assessing transvascular denervation

ABSTRACT

A catheter apparatus for assessing denervation comprises: an elongated catheter body; a deployable structure coupled to the catheter body, the deployable structure being deployable outwardly from and contractible inwardly toward the longitudinal axis of the catheter body; one or more ablation elements disposed on the deployable structure to move outwardly and inwardly with the deployable structure; one or more stimulation elements spaced from each other and disposed on the deployable structure to move with the deployable structure, the stimulation elements being powered to supply nerve stimulating signals to the vessel; and one or more recording elements spaced from each other and from the stimulation elements, the recording elements being disposed on the deployable structure to move with the deployable structure, the recording elements configured to record response of the vessel to the nerve stimulating signals.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/153,838, filed Jun. 6, 2011, now U.S. Pat. No. 8,909,316, which is acontinuation-in-part of U.S. patent application Ser. No. 13/110,041,filed May 18, 2011, now abandoned, each of which are incorporated hereinby reference in their entireties.

BACKGROUND OF THE INVENTION

The present invention relates generally to catheter devices, and morespecifically to catheter devices for assessing transvasculardenervation.

Renal denervation is a method whereby amplified sympathetic activitiesare suppressed to treat hypertension or other cardiovascular disordersand chronic renal diseases. The objective of renal denervation is toneutralize the effect of renal sympathetic system which is involved inarterial hypertension. The following describes some examples of renaldenervation devices. U.S. Pat. No. 7,653,438 discloses renalneuromodulation using a pulsed electric field to effectuateelectroporation or electrofusion. It describes percutaneousintravascular delivery of pulsed electric fields to achieve renalneuromodulation. U.S. Patent Application Publication No. 2010/0268307discloses intravascularly induced neuromodulation using a pulsedelectric field to effectuate irreversible electroporation orelectrofusion, necrosis, and/or inducement of apoptosis, alteration ofgene expression, changes in cytokine upregulation, etc., in targetneural fibers. It mentions the use of the technique to modulate a neuralfiber that contributes to renal function. International PatentPublication No. WO2008/092246 discloses transvascular nerve stimulationthrough the walls of blood vessels. It uses electrodes supported on anelectrically insulating backing sheet and a structure for holding thebacking sheet against the inner wall of the blood vessel.

Catheters are flexible, tubular devices that are widely used byphysicians performing medical procedures to gain access into interiorregions of the body. A catheter device can be used for ablating renalsympathetic nerves in therapeutic renal sympathetic denervation toachieve reductions of blood pressure in patients suffering from renalsympathetic hyperactivity associated with hypertension and itsprogression. See, e.g., Henry Krum et al., Catheter-Based RenalSympathetic Denervation for Resistant Hypertension: A Multicentre Safetyand Proof-of-Principle Cohort Study, published online Mar. 30, 2009 atwww.thelancet.com.

Renal arteries, like all major blood vessels, are innervated byperivascular sympathetic nerves that traverse the length of thearteries. The perivascular nerves consist of a network of axons,terminals, and varicosities, which are distributed mostly in themedial-adventitial and adventitial layers of the arterial wall. Themedial and adventitial layers of the renal artery consist mostly ofvascular smooth muscle cells (VSMCs), while the intimal layer is made upof endothelial cells (ECs). A small percentage of the VSMCs in theadventitia of the renal artery have a direct coupling to thevaricosities because of their proximity to each other. When the renalsympathetic nerve is stimulated and an action potential travels alongthe axon, all varicosities along the axon are depolarized andneurotransmitters are released into the junctions of directly-coupledVSMCs. This event causes the opening of specific ionic and secondmessenger molecule channels of the VSMCs and results in theirdepolarization.

The depolarization described above would normally be confined to thefirst layer of the VSMCs that are directly coupled to the varicositiesbecause extracellular diffusion of neurotransmitters is characterized bya small space and time constant. Therefore in theory any recording ofexcitatory junction potentials (EJPs) should be done at the directlycoupled VSMCs. However, numerous studies of vasomotion of arteries haveled to the understanding that additional VSMCs are recruited ingenerating a syncytial response to neural stimulation. Thus gapjunctions have been identified amongst VSMCs and ECs, and between VSMCsand ECs. These gap junctions form the conduit for intercellularcommunication and facilitate neurotransmitter diffusion over a largerspace constant than can be accounted for by extracellular diffusionalone. Intercellular diffusion is dependent on gap junction permeabilityand decays as it crosses each junction. Recording of EJPs have beenshown to take place within a few millimeters from perivascular nerves.

EJP recordings are commonly performed using intracellular techniques.The recording electrodes are typically made of glass micropipettes thatimpale a single cell to provide an isolated signal path to an amplifier.In other techniques, suction is applied to provide a high impedance sealbetween the glass micropipette and cell membrane without having topenetrate the cell. The high impedance seal isolates signal conductionbetween the cell membrane and the electrode from environmental noise.Extracellular recording of junction potentials are possible but morechallenging because of the much smaller potential amplitude at thesurface of the cell and the electronics requirements for noisereduction. Depending on the size of the recording electrode,extracellular recording may record from a single cell or an ensemble ofcells. The latter is analogous to field potential recording frommulti-neurons in the brain.

In certain animal arteries such as rat tail arteries and mesentericarteries, recording of spontaneous EJPs (SEJPs) have been reported.These SEJPs occur asynchronously following normal sympathetic activitiesof the animal physiology. On average the recording of these asynchronousSEJPs will cancel out within a field potential recording technique,regardless of the fidelity of the recording electronics. On the otherhand, when perivascular nerves are stimulated under external control,EJPs occur synchronously with the stimulus source, thus enabling evokedresponses to be detected in the recording. Common techniques forelectrical perivascular nerve stimulation include both nerve trunkstimulation and transmural (field) stimulation. Both techniques requiredirect electrode access to the adventitial area of the artery. Withtransmural stimulation, the stimulus strengths are designed to besupramaximal to activate the perivascular nerves without directlystimulating the VSMCs.

Transvascular technique of electrical stimulation of perivascular nervesis not as widely reported. One possible explanation is the stimulusstrength required to activate the perivascular nerves will most likelyalso stimulate the VSMCs directly (this is because the electricalcurrent density from the electrode attenuates as a function of distanceand the VSMCs are closer to the stimulating electrodes than theperivascular nerves), thus making it difficult to analyze neurallyevoked responses independently. Most electrical stimulus consists ofsquare pulses and by using shorter pulse widths it may be possible toselectively activate the perivascular nerves only. However, a bettermethod is to make use of the anisotropy of VSMCs and the finite spaceconstants of EJPs to differentiate neurally evoked responses from fieldevoked responses, so that perivascular nerve integrity can beindependently assessed. Thus in a preferred arrangement, the stimulatingelectrodes and recording electrodes should be separated by a distancegreater than the EJP space constant in the longitudinal direction of thevessel. In this way, the recording electrodes will only record EJPsevoked by action potentials traveling distally along the axon, whileexcluding EJPs evoked in the vicinity of the stimulating electrodes.

BRIEF SUMMARY OF THE INVENTION

Prior denervation devices do not provide any means of predicting thelong term outcome of the renal denervation therapies. Nor do theyprovide a marker to assess the completeness of the therapeuticprocedure. In the case where denervation is carried out by deliveringcontinuous RF energy through the vascular wall, the typical targetprocedural parameters are impedance, elapsed time, temperature or power,or a combination of all the above. The correlation of these parameterswith the extent of denervation has never been shown, and may not betenable given the heterogeneous nature of vascular innervationstructures. There is therefore a need to provide a more direct techniqueof measuring residual neural activities following denervation in orderto assess the completeness of such procedures.

Exemplary embodiments of the invention provide catheter devices forassessing transvascular denervation. The patency of the innervation ofvessels can be assessed directly through electrophysiologicaltechniques. Specifically, appropriately positioned sensors are deployedin direct contact with the vessel luminal wall to record evokedresponses from external stimulus. Excitatory junctional potentials fromthe VSMCs can be recorded. Mechanical responses (vasoconstriction orvasodilation) associated with these neural events can also be monitored.By comparing the pre-treatment recording with post-treatment recording,a DeNervation Assessment index (DNAi) can be derived.

In accordance with an aspect of the present invention, a catheterapparatus for assessing denervation comprises: an elongated catheterbody having a proximal end and a distal end, a longitudinal axisextending in a longitudinal direction between the distal end and theproximal end; a deployable structure coupled to the catheter body, thedeployable structure being deployable outwardly from the longitudinalaxis and contractible inwardly toward the longitudinal axis of thecatheter body; one or more ablation elements disposed on the deployablestructure to move outwardly and inwardly with the deployable structure,the one or more ablation elements being powered to apply ablation energyto a vessel of a patient; one or more stimulation elements spaced fromeach other and disposed on the deployable structure to move outwardlyand inwardly with the deployable structure, the one or more stimulationelements being powered to supply nerve stimulating signals to thevessel; and one or more recording elements spaced from each other andfrom the one or more stimulation elements, the one or more recordingelements being disposed on the deployable structure to move outwardlyand inwardly with the deployable structure, the one or more recordingelements configured to record response of the vessel to the nervestimulating signals.

In some embodiments, the one or more stimulation elements are proximalrelative to the one or more recording elements. A most distal ablationelement of the one or more ablation elements is no more distal than atleast one of the stimulation elements and a most proximal ablationelement of the one or more ablation elements is no more proximal than atleast one of the one or more recording elements. At least one of theablation elements is also a stimulation element or a recording element.Some of the one or more recording elements are spaced from one of theone or more stimulation elements by one of a longitudinal spacing, alateral spacing, or a combined longitudinal and lateral spacing. The oneor more recording elements are configured to record one or more ofevoked electrical responses or mechanical responses of the vessel inresponse to the nerve stimulating signals.

In specific embodiments, the deployable structure comprises a pluralityof longitudinal spines, each of the spines having a proximal endconnected to the catheter body and a distal end connected to thecatheter body. Each spine includes an elbow having at least onediscontinuity in stiffness at an intermediate position between thedistal end and the proximal end thereof. The one or more ablationelements, the one or more stimulation elements, and the one or morerecording elements are disposed on the spines. The deployable structureis contractible to a contracted arrangement to fit within a lumen of theelongated catheter body and is deployable to a deployed arrangement withthe elbows of the spines bending outwardly relative to the proximal anddistal ends of the spines, the elbows of the spines moving radiallyoutwardly from the contracted arrangement to the deployed arrangement.The catheter apparatus further comprises a balloon disposed inside thedeployable structure, the spines being disposed radially outwardlyrelative to the balloon, the balloon inflating to move the spinesradially outwardly in the deployed arrangement and deflating in thecontracted arrangement. One or more contact sensors are disposed on asurface of the balloon for measuring force or pressure.

In some embodiments, the deployable structure comprises a balloon madeof an electrically insulative material, the balloon inflating to moveradially outwardly relative to the catheter body in a deployedarrangement and deflating in an undeployed arrangement. The one or moreablation elements, one or more stimulation elements, and one or morerecording elements are disposed on a surface of the balloon. Anintraluminal pressure sensor is to be introduced and deployed inside theballoon for pressure monitoring.

In specific embodiments, the deployable structure comprises a deployablesleeve made of an electrically insulative material and a hollow tubingdisposed inside the deployable sleeve. The hollow tubing includes aplurality of holes for fluid to pass therethrough to push the deployablesleeve radially outwardly relative to the catheter body in a deployedarrangement. The one or more ablation elements, the one or morestimulation elements, and the one or more recording elements aredisposed on a surface of the deployable sleeve. The catheter apparatusfurther comprises a plurality of draw strings extending from inside thehollow tubing through the holes to the deployable sleeve to draw thedeployable sleeve radially inwardly relative to the catheter body in anundeployed arrangement. The deployable structure is contractible to acontracted arrangement and is deployable to a deployed arrangement. Thedeployable structure includes an anti-occlusion feature to permit fluidflow in the vessel between a proximal end and a distal end of thedeployable structure in the deployed arrangement.

In accordance with another aspect of the invention, a catheter apparatusfor assessing denervation comprises: an elongated catheter body having aproximal end and a distal end, a longitudinal axis extending in alongitudinal direction between the distal end and the proximal end; astructure coupled to the catheter body; one or more ablation elementsdisposed on the structure and being powered to apply ablation energy toa vessel of a patient; one or more stimulation elements spaced from eachother and disposed on the structure, the one or more stimulationelements being powered to supply nerve stimulating signals to thevessel; one or more recording elements spaced from each other and fromthe one or more stimulation elements, the one or more recording elementsbeing disposed on the structure and configured to record response of thevessel to the nerve stimulating signals; and a mechanism to deploy thestructure outwardly from the longitudinal axis of the catheter body tomove the ablation elements, the one or more stimulation elements, andthe one or more recording elements outwardly to a deployed arrangement,and to contract the structure inwardly toward the longitudinal axis ofthe catheter body to move the ablation elements, the one or morestimulation elements, and the one or more recording elements inwardly toa contracted arrangement.

In accordance with another aspect of this invention, a method ofassessing denervation comprises: introducing intravascularly a catheterto a vessel of a patient, the catheter including one or more recordingelements; performing a baseline recording of responses by supplyingnerve stimulation to the vessel and recording responses of the vessel tothe nerve stimulation; denervating at least some tissue proximate thevessel after performing the baseline recording; performing apost-denervation recording of responses, after the denervating, bysupplying nerve stimulation to the vessel and recording responses of thevessel to the nerve stimulation; and assessing denervation of the vesselbased on a comparison of the responses of the baseline recording and theresponses of the post-denervation recording.

In some embodiments, the catheter is not repositioned during performingthe baseline recording, denervating, and performing the post-denervationrecording. The nerve stimulation comprises one of electrical stimulationor pharmacological stimulation. The responses include one or more ofelectrical response or mechanical response. Assessing denervation of thevessel comprises: computing a baseline parameter from the responses ofthe baseline recording; computing a post-denervation parameter from theresponses of the post-denervation recording; and computing a degree ofdenervation as a ratio of the post-denervation parameter and thebaseline parameter. Denervation is achieved when the computed ratiofalls within a preset range. The baseline parameter is computed based ona baseline maximum signal amplitude of one or more evoked responsesgenerated in response to the nerve stimulation and recorded by the oneor more recording elements before the denervating. The post-denervationis computed based on a post-denervation maximum signal amplitude of oneor more evoked responses generated in response to the same nervestimulation and recorded by the one or more recording elements after thedenervating. The one or more evoked responses include one or more ofevoked electrical response or evoked mechanical response.

In specific embodiments, the baseline parameter is computed based on abaseline area under a plot of one or more evoked responses generated inresponse to the nerve stimulation and recorded by the one or morerecording elements before the denervating. The post-denervation iscomputed based on a post-denervation area under a plot of one or moreevoked responses generated in response to the same nerve stimulation andrecorded by the one or more recording elements after the denervating.The method further comprises, if denervation of the vessel is notachieved, repeating the steps of denervating, performing apost-denervation recording of responses, and assessing denervation ofthe vessel until denervation of the vessel is achieved. The repeatinguntil denervation of the vessel is achieved is performed in real time.The catheter is not repositioned during the repeating. Repeating thesteps of denervating, performing a post-denervation recording ofresponses, and assessing denervation of the vessel comprises adjusting alevel of denervation for denervating at least some tissue proximate thevessel based on result of assessing denervation of the vessel. Therepeating including the adjusting until denervation of the vessel isachieved is performed in real time.

In some embodiments, recording responses of the vessel to the nervestimulation comprises recording one or more of evoked electricalresponses or mechanical responses of the vessel in response to the nervestimulation. The vessel is denervated using one or more ablationelements disposed on the catheter. The catheter is not repositionedduring performing the baseline recording, denervating, and performingthe post-denervation recording. The catheter includes one or morestimulation elements to supply nerve stimulating signals as the nervestimulation.

In specific embodiments, the method further comprises deploying adeployable structure to enhance contact between the one or morestimulation elements and the vessel and between the one or morerecording elements and the vessel. The method further comprisesproviding electrical insulation between the one or more stimulationelements and the one or more recording elements to facilitate signalconduction between the one or more stimulation elements and tissueproximate the vessel and to facilitate signal conduction between the oneor more recording elements and tissue proximate the vessel. The methodfurther comprises deploying a deployable structure to enhance contactbetween the one or more recording elements and the vessel.

These and other features and advantages of the present invention willbecome apparent to those of ordinary skill in the art in view of thefollowing detailed description of the specific embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an elevational view of a catheter device with a deployablebasket for assessing transvascular denervation according to anembodiment of the present invention.

FIG. 2 is an elevational view of a catheter device with aballoon-augmented deployable basket according to another embodiment ofthe present invention.

FIG. 3 is an elevational view of a catheter device with a deployableballoon according to another embodiment of the present invention.

FIG. 4 is a perspective view of a catheter device with a deployablesleeve according to another embodiment of the present invention.

FIGS. 5A-5F show different configurations of the stimulating andrecording electrodes of the deployable sleeve of FIG. 4.

FIG. 6 is a perspective view of a partially cut-out section of thecatheter device of FIG. 4.

FIG. 7 is a schematic view illustrating an apparatus to provide anintraluminal pressure sensor for use with the catheter device.

FIG. 8 is a perspective view of a catheter device with a deployablesleeve having an anti-occlusion feature according to another embodimentof the present invention.

FIGS. 8A and 8B are elevational views of a catheter device with adeployable sleeve having an anti-occlusion feature according to anotherembodiment of the present invention.

FIG. 9 shows an example of a flow diagram illustrating a method forassessing transvascular denervation.

FIG. 10 shows an example of a plot of evoked responses and stimulusartifacts recorded by the recording elements.

DETAILED DESCRIPTION OF THE INVENTION

In the following detailed description of the invention, reference ismade to the accompanying drawings which form a part of the disclosure,and in which are shown by way of illustration, and not of limitation,exemplary embodiments by which the invention may be practiced. In thedrawings, like numerals describe substantially similar componentsthroughout the several views. Further, it should be noted that while thedetailed description provides various exemplary embodiments, asdescribed below and as illustrated in the drawings, the presentinvention is not limited to the embodiments described and illustratedherein, but can extend to other embodiments, as would be known or aswould become known to those skilled in the art. Reference in thespecification to “one embodiment”, “this embodiment”, or “theseembodiments” means that a particular feature, structure, orcharacteristic described in connection with the embodiment is includedin at least one embodiment of the invention, and the appearances ofthese phrases in various places in the specification are not necessarilyall referring to the same embodiment. Additionally, in the followingdetailed description, numerous specific details are set forth in orderto provide a thorough understanding of the present invention. However,it will be apparent to one of ordinary skill in the art that thesespecific details may not all be needed to practice the presentinvention. In other circumstances, well-known structures, materials,circuits, processes and interfaces have not been described in detail,and/or may be illustrated in block diagram form, so as to notunnecessarily obscure the present invention.

In the following description, relative orientation and placementterminology, such as the terms horizontal, vertical, left, right, topand bottom, is used. It will be appreciated that these terms refer torelative directions and placement in a two dimensional layout withrespect to a given orientation of the layout. For a differentorientation of the layout, different relative orientation and placementterms may be used to describe the same objects or operations.

Exemplary embodiments of the invention, as will be described in greaterdetail below, provide apparatuses and methods for assessingtransvascular denervation.

FIG. 1 is an elevational view of a catheter device with a deployablebasket for assessing transvascular denervation according to anembodiment of the present invention. The device integrates neuralassessment elements with denervation elements for renal denervation orthe like. In the specific embodiment shown, the denervation elements areconfigured as ablation electrodes. In other embodiments, theablation/denervation element may employ other mechanisms or other typesof energy (e.g., laser, high intensity focused ultrasound (HIFU),cryoablation, mechanical) to sever or interrupt conduction of the nervefibers. FIG. 1 shows ablation electrodes 11, 12, 13, 14 and additionalelectrodes 15, 16 which are disposed on spines 20 in a deployablestructure in a basket configuration 30 which is coupled to a catheterbody 40. The catheter body 40 has a proximal end 42, a distal end 44,and a longitudinal axis extending in a longitudinal direction betweenthe distal end 44 and the proximal end 42. An external catheter handle46 is provided at the proximal end. The spines 20 are electricallynonconductive.

In this embodiment, the deployable basket 30 is coupled to the distalportion of the catheter body 40, and is deployable or expandableoutwardly from the longitudinal axis and contractible inwardly towardthe longitudinal axis of the catheter body 40. The basket 30 has aplurality of longitudinal spines 20 having distal ends and proximal endsthat are attached to the catheter body 40. Each spine 20 includes anelbow having at least one discontinuity in stiffness at an intermediateposition between the distal end and the proximal end thereof to allowthe spine to expand/deploy and collapse/contract. Different mechanismscan be used to cause the expansion and collapse of the spines 20. InFIG. 1, a pull wire 50 extending along the longitudinal axis of thecatheter body 40 is used to pull the distal end of the basket 30 in theproximal direction to deploy the basket 30. The basket 30 is in adeployed configuration in FIG. 1. To return the basket 30 to acontracted/undeployed configuration with the spines 20 extendinggenerally longitudinally in the longitudinal direction, the spines 20can be resiliently biased toward the contracted configuration and thepulling force on the pull wire 50 can be released to allow the basket 30to contract. Alternatively, the pull wire 50 may be configured to applya push force to push the distal end of the basket 30 in the distaldirection to contract the basket 30. In a specific embodiment, thebasket 30 is contractible to a contracted arrangement to fit within alumen of the elongated catheter body 40 and is deployable to a deployedarrangement with the elbows of the spines bending outwardly relative tothe proximal and distal ends of the spines 20, the elbows of the spinesmoving radially outwardly from the contracted arrangement to thedeployed arrangement. An example of a similar deployable basket is foundin US 2010/0076426 entitled Basket Catheter Having Multiple Electrodes,which is incorporated herein by reference in its entirety.

The pull wire 50 extends through a lumen of the catheter body 40. Thelumen can also accommodate lines for supplying power to ablationelectrodes, signals lines to stimulation electrodes and recordingelectrodes, fluid lines, and the like.

The electrodes 11, 12, 13, 14, 15, 16 are disposed on the deployablebasket 30 to move outwardly and inwardly with the basket 30. Theablation electrodes 11, 12, 13, 14 are powered to apply ablation energyto a vessel of a patient such as a renal artery. Any of the ablationelectrodes can also be stimulation or recording electrodes. Stimulationelectrodes are powered to supply nerve stimulating signals to thevessel. The nerve stimulating signals are typically about 1 Hz to about16 Hz and are designed to cause nerve excitation and evokeneurotransmitter release from perivascular varicosities. The stimulationthresholds will likely be much smaller than those for neuromodulation astaught in the art, since the intent is not to irreversibly electroporatethe nerves. Recording electrodes are configured to record response ofthe vessel to the nerve stimulating signals. In some preferredembodiments, the recording electrodes are configured to record one ormore of evoked electrical responses or mechanical responses of thevessel in response to the nerve stimulating signals. The stimulationelectrodes are spaced from each other, the recording electrodes arespaced from each other, and the stimulation electrodes are spaced fromthe recording electrodes. As seen in FIG. 1, the spacing between theelectrodes can be longitudinal, lateral/circumferential, or acombination of the two. Several stimulation and recording configurationsare possible in FIG. 1. A first example includes stimulation electrodes13, 15 and recording electrodes 14, 16 and 11, 12. A second exampleincludes stimulation electrodes 14, 16 and recording electrodes 13, 15,and 11, 12. A third example includes stimulation electrodes 11, 12 andrecording electrodes 13, 15 and 14, 16. In some preferred embodiments,at least some of the stimulation electrodes are proximal relative to atleast some of the recording electrodes. The stimulation electrodes 14,16 are separated from the recording electrodes 11, 12, 13, 15 by atleast a minimum distance, which is preferably approximately equal to thespace constant of excitatory junction potentials (EJPs).

Nerve stimulation is preferably applied along the long axis of thevessel or artery since the nerve cells are aligned in that direction. Todetect evoked responses, however, we are interested in the VSMCs whichare aligned transverse to the nerves and hence the recording bipolarelectrodes will preferably be oriented in the transverse directionaccordingly. More particularly, the apparatus is set up to record fromdifferent configurations and orientations of electrodes simultaneouslyin order to maximize the likelihood of detection.

In FIG. 1, ablation is performed with two distal electrodes (11, 12) andtwo proximal electrodes (13, 14). Neural assessment is performed with acombination of the four ablation electrodes (11, 12, 13, 14) which alsoserve as stimulation or recording electrodes and two additional sensorelectrodes (15, 16). In neural assessment, stimulating electrodes aretypically parallel to the long axis of the vessel, while recordingelectrodes are made up of both transverse pairs and parallel pairs tothe long axis of the vessel. Stimulation and recording typically involveseparate sets of electrodes, but can be configured for simultaneousstimulation and recording with appropriate electronics circuits.Stimulation and recording can be performed using bipolar electrodes asshown in FIG. 1. Alternatively, monopolar and multipolar techniques canbe used. For monopolar stimulation or recording, only one activeelectrode is required and an indifferent electrode is provided on thepatient's tissue. Ablation is typically performed monopolarly, butbipolar or multipolar ablations are also possible with a differentelectrode arrangement. In some preferred embodiments, the most distalablation electrode (11 or 12) is no more distal than at least one of thestimulation electrodes and the most proximal ablation electrode (13 or14) is no more proximal than at least one of the recording electrodes.

FIG. 2 is an elevational view of a catheter device with aballoon-augmented deployable basket according to another embodiment ofthe present invention. This embodiment is similar to that of FIG. 1 withthe addition of an elongated balloon 60 inside the basket 30 to replacethe pull-wire expansion mechanism 50. It inflates to expand the basket30 outwardly in the deployed arrangement and deflates in thecontracted/undeployed arrangement. This embodiment enhances tissue andelectrode contact for both ablation and neural assessment. Theballoon-augmented catheter is first deflated and positioned at thetarget renal artery site. Then the balloon 60 is inflated with saline orthe like to a preset volume for neural assessment and ablation. Theballoon 60 is preferably made of an electrically insulative material,which facilitates signal conduction between the stimulation electrodesand the tissue proximate the vessel and to facilitate signal conductionbetween the recording electrodes and the tissue proximate the vessel.The electrically insulative balloon 60 preferably permits the leastresistive path for signal conduction between the stimulation electrodesand the tissue and between the recording electrodes and the tissue.

The contact force or pressure between the vessel wall and the balloon 60is transmitted to the fluid inside the balloon 60 and measuredproximally at the external catheter handle 46 via suitable instruments;alternatively, additional electromechanical contact force/pressuresensors 66 can be incorporated on the surface of the balloon 60 torecord changes in the luminal wall force/pressure. FIG. 2 shows acircumferential band of contact force/pressure sensors 66, but othersensor configurations are possible. The method of mechanical sensinghere is advantageous since it is less susceptible to interference withthe source of stimulus which is of a different modality (electrical).The balloon 60 may be made of a variety of materials including, forexample, polyurethane or nylon.

FIG. 3 is an elevational view of a catheter device with a deployableballoon according to another embodiment of the present invention. Thisembodiment is similar to that of FIG. 2 but eliminates the basket andemploys a balloon 70 with integrated electrodes. The electrodes may beembedded with the balloon material or printed on through a thin filmdeposition process. For simplicity, FIG. 3 shows a similar set ofelectrodes 11, 12, 13, 14, 15, 16 and force/pressure sensors 66 as thosein FIGS. 1 and 2. The balloon 70 may have some or all of the samefeatures and characteristics as the balloon 60 of FIG. 2 as describedabove.

FIG. 4 is a perspective view of a catheter device with a deployablesleeve according to another embodiment of the present invention. Thisembodiment makes use of a deployable sleeve 80 instead of a balloon toinsulate the electrodes from the blood in the vessel. The sleeve 80 ispreferably made of an electrically insulating material. Variousarrangements of electrodes for ablation and assessing denervation can beutilized. As an example, a spiral strip (not shown) of ablationelectrode can be attached to the outside of the sleeve 80 and along thelong axis of the sleeve 80. Alternatively, the single strip may bedivided into multiple ablation electrodes 82 connected in series to forma spiral arrangement along the outside of the sleeve 80. This is thearrangement, for example, when monopolar ablation is desired and outputpower is divided equally across all ablation electrodes. Alternatively,ablation can be performed preferentially by bipolar means. In this case,pairs of electrodes can be grouped to create bipolar lesions that arelarger and more contiguous than if monopolar lesions were created. Aplurality of bipolar sets of stimulation electrodes 84 (FIGS. 4 and5A-5F show three pairs each being parallel to the long axis of thesleeve 80) and a plurality of recording electrodes 86 (FIGS. 4 and 5A-5Fshow three) are attached to each side of the ablation electrodes 82respectively. The three pairs of stimulation electrodes 84 aredistributed circumferentially to provide circumferential coverage ofnerves. Each pair of stimulating electrodes 84 can be energized to evokeresponses to be recorded with the recording electrodes 86.

FIGS. 5A-5F show different configurations of the stimulating andrecording electrodes of the deployable sleeve 80 of FIG. 4. Theelevational view of FIG. 5A and the end view of FIG. 5B (from proximalend) illustrate the arrangement of the three pairs of stimulatingelectrodes 84 and three recording electrodes 86. The ablation electrodesare omitted for simplicity. FIG. 5C shows a recording configuration withthe first pair of stimulation electrodes 84 active (other pairs areomitted for simplicity). The active stimulation electrodes 84 andrecording electrodes 86 are connected to recording amplifiers 88. FIG.5D shows a recording configuration with the second pair of stimulationelectrodes 84 active (other pairs are omitted for simplicity). FIG. 5Eshows a recording configuration with the third pair of stimulationelectrodes 84 active (other pairs are omitted for simplicity). FIG. 5Fshows a recording configuration with all three pairs of stimulationelectrodes 84 active. A total of three contiguous stimulation-recordingperiods can be performed, for both baseline and post-denervationassessments. Alternatively, all three stimulating electrode pairs 86 areenergized simultaneously, while evoked responses are recorded betweeneach recording electrode 86 and an indifferent electrode or electronicground.

Lead wires for all the electrodes as well as thermocouple wires areembedded within the sleeve substrate. During ablation the ablationelectrode circuit is closed, while the neural assessment electrodecircuit is open. Following ablation, the opposite is true for neuralassessment, i.e., the ablation electrode circuit is open, and the neuralassessment electrode circuit is closed. Additional electromechanicalsensors for force/pressure sensing and the like can likewise beincorporated as the sensors 66 on the balloons 60, 70 of FIGS. 2 and 3.The sleeve 80 may be made of a variety of materials including, forexample, polyurethane or nylon.

FIG. 6 is a perspective view of a partially cut-out section of thecatheter device of FIG. 4. The sleeve 80 is moved between a deployedarrangement and a contracted/undeployed arrangement using any suitablemechanism. The sleeve 80 is open and non-occlusive, except for themechanism of deploying and contracting. In the example seen in FIG. 6,the sleeve 80 is contracted using three sets of draw strings 90 locatednear the distal and proximal ends as well as midpoint of the sleeve 80.The draw strings 90 are drawn into a hollow tubing 92, which is cappedat the distal end, through the holes 94 per draw string 90. All threedraw strings 90 are joined together at a proximal distance by a pullwire 96 that is controlled at the proximal catheter handle 46. Torelease the draw strings 90, the handle 46 will first advance the pullwire 96 to relax the draw strings 90, and then a bolus of saline or thelike is injected through the tubing 92 creating an outward pressure atthe draw string holes 94 (and optionally additional holes) and forcesthe sleeve 80 to expand towards the vascular wall, thus insulating theelectrodes from the vessel. To move the sleeve 80 to the contractedarrangement, the pull wire 96 is retracted at the handle 46 to pull thedraw strings 90 to draw the sleeve 80 radially inwardly. Thenon-occlusive sleeve 80 is deployed by exerting a positive differentialpressure by the injected fluid against the blood in the vessel, and oncedeployed, is kept in place (i.e., in contact with vessel wall) by theblood pressure. In the reverse action of contracting, the draw strings90 are retracted into the hollow tubing 92 by the pull wire 96, havingovercome the positive blood pressure exerted against the sleeve 80.

FIG. 7 is a schematic view illustrating an apparatus to provide anintraluminal pressure sensor for use with the catheter device. In theembodiment shown, the intraluminal pressure sensor 100 is introducedproximally and deployed inside the balloon 102 (which may be balloon 60of FIG. 2 or balloon 70 of FIG. 3) for pressure monitoring whilemaintaining the balloon 102 isovolumic. The apparatus of FIG. 7 includesan analyzer 106 coupled to the pressure sensor 100, a syringe 110 and afluid port 112 for introducing a fluid into the balloon 102, and anelectrical port 116 for supplying electrical energy to the catheterdevice. This provides an alternative or an additional mechanism forpressure sensing while maintaining the balloon 102 isovolumic.

FIG. 8 is a perspective view of a catheter device with a deployablesleeve having an anti-occlusion feature according to another embodimentof the present invention. This embodiment is similar to that of FIGS. 4and 5 but the sleeve structure is modified to provide an anti-occlusionfeature to permit blood/fluid flow in the vessel between the proximalend and the distal end of the deployable sleeve structure in thedeployed arrangement. In FIG. 8, the sleeve 120 remains flexible and haselectrodes similar to those in FIG. 4. A plurality of rib channels 122are used to connect the lumen of the hollow tubing 92 to an enclosedinterior of sleeve 120 between its outer shell 124 and inner shell 126.The interior of the sleeve 120 and the rib channels 122 are capped orclosed at the proximal and distal ends. The inner shell 126 of thesleeve 120 is preferably noncompliant so that it does not stretch orexpand beyond its preset expanded shape. The outer shell 124 of thesleeve 120 is preferably semi-compliant so that it can stretch under thepressure of the fluid supplied to the interior of the sleeve 120 toenhance contact between the electrodes and the vessel wall. The ribchannels 122 span the length of the sleeve 120 and are preferablyflexible but noncompliant. Open flow paths are provided between the ribchannels 122 to permit fluid flow in the vessel between the proximal endand the distal end of the sleeve 120 in the deployed arrangement.

FIGS. 8A and 8B are elevational views of a catheter device with adeployable sleeve having an anti-occlusion feature according to anotherembodiment of the present invention. The sleeve 202 is undeployed inFIG. 8A and deployed in FIG. 8B. The sleeve 202 is connected or bondedto a set of distal spines 206 and a set of proximal spines 208. Thedistal spines 206 are connected between a distal termination end 210 anda distal retainer 212. The proximal spines 208 are connected between aproximal retainer 214 and a proximal termination end 216. The distaltermination end 210 and proximal termination end 216 are both fixed tothe catheter body 218, and are hence separated by a fixed distance. Aresilient member such as a spring 220 is connected between the distalretainer 212 and the proximal retainer 214. A wire 222, which is a pullwire or a push-pull wire, is fixed at one end to a wire anchor 226 onthe proximal retainer 214 and loops through holes in the proximalretainer 214 and the distal retainer 212 to the proximal portion of thecatheter body 218. In FIG. 8A, the wire 222 is pulled to produce apre-compressed spring 220. The distal spines 206 and proximal spines 208as well as the sleeve 202 are in the collapsed/contracted/undeployedstate. FIG. 8B shows the distal spines 206, proximal spines 208, andsleeve 202 in the expanded/deployed state. By releasing the tension onthe wire 222, the spring 220 stretches, thereby pushing the distalretainer 212 and proximal retainer 214 apart. The distal retainer 212moves toward the distal termination end 210 and the proximal retainer214 moves toward the proximal termination end 216. This causes thedistal spines 206 and the proximal spines 208 to expand laterally anddeploy the sleeve 202 radially outwardly. The ends of the sleeve 202 areopen in the deployed state of FIG. 8B, thereby allowing fluid flow inthe vessel between the proximal end and the distal end of the sleeve 202in the deployed arrangement without occlusion.

Other configurations of deployable structures and features can be used.For example, a deployable structure may be formed by a plurality oflongitudinal strips that can be pulled in the longitudinal directiontoward a straight configuration in the contracted/undeployedarrangement. When the pulling force is removed, the longitudinal stripsexpand radially outwardly into a spiral configuration in the deployedarrangement, for instance, under a resilient biasing force such as amemory shape material. Another example of a deployable structure is anS-shaped structure having one or more stimulating elements at the distalend thereof, one or more ablation elements on the first/distal hump ofthe S-shaped structure from the distal end thereof, and one or morerecording elements on the second/proximal hump of the S-shaped structurefrom the distal end thereof. The S-shaped structure is preformed intothe S-shape (e.g., using a shape memory material). It isstretched/deformed toward a straight configuration (e.g., using astylet) in the contracted arrangement and is allowed to return to theS-shape in the deployed arrangement.

FIG. 9 shows an example of a flow diagram illustrating a method forassessing transvascular denervation. To assess transvascular denervationusing the apparatus described above, a user introduces intravascularlyany of the above catheter devices to a target vessel of a patient anddeploys it (step 902), and performs a baseline recording of responses bysupplying nerve stimulating signals to the vessel with the stimulationelectrodes and records responses of the vessel to the nerve stimulatingsignals using the recording electrodes (step 904). Next, the ablationelectrodes are activated to ablate/denervate at least some tissueproximate the vessel (step 906). The user then performs a post-ablationrecording of responses, after the denervating, by supplying nervestimulating signals to the vessel with the stimulation electrodes andrecords responses of the vessel to the nerve stimulating signals usingthe recording electrodes (step 908). The user can assess denervation ofthe vessel based on a comparison of the responses of the baselinerecording and the responses of the post-ablation recording (step 910).For stimulation and recording, it is preferable to deploy or expand adeployable structure (e.g., basket, balloon, sleeve, or the like) toenhance contact between the stimulation electrodes and the vessel walland between the recording electrodes and the vessel wall.Ablation/denervation elements are preferably provided on the catheterdevice. As such, it is not necessary to reposition the catheter duringthe baseline recording, the ablation, and the post-ablation recording.

The responses include, for example, electrical response and/ormechanical response, which can be evoked excitatory junctionalpotentials or wall tension of the vessel in response to the nervestimulating signals. In general, assessing denervation of the vesselincludes computing a baseline parameter from the responses of thebaseline recording, computing a post-ablation parameter from theresponses of the post-ablation recording, and computing a degree ofdenervation as a ratio of the post-ablation parameter and the baselineparameter. The desired denervation is achieved when the computed ratiofalls within a preset range. In one example, the baseline parameter iscomputed based on a baseline maximum signal amplitude of one or moreevoked responses generated in response to stimulation of nervestimulating signals by the stimulation elements and recorded by therecording elements before the ablating, and the post-ablation iscomputed based on a post-ablation maximum signal amplitude of one ormore evoked responses generated in response to the same stimulation ofnerve stimulating signals by the stimulation elements and recorded bythe recording elements after the ablating. The evoked responses mayinclude evoked electrical response and/or evoked mechanical responsesuch as can be detected with a pressure sensor. In another example, thebaseline parameter is computed based on a baseline area under a plot ofone or more evoked responses generated in response to stimulation by thestimulation elements and recorded by the recording elements before theablating, and the post-ablation is computed based on a post-ablationarea under a plot of one or more evoked responses generated in responseto the same stimulation by the stimulation elements and recorded by therecording elements after the ablating. FIG. 10 shows an example of aplot of evoked responses and stimulus artifacts recorded by therecording elements. The evoked responses each have an amplitude and anarea. For multiple evoked responses, an average of the amplitudes or anaverage of the areas may be used to calculate the parameter.

If denervation of the vessel is not achieved, the user can repeat thesteps of denervating (step 906), performing a post-ablation recording ofresponses (step 908), and assessing denervation of the vessel (step 910)until denervation of the vessel is achieved. The catheter need not berepositioned during the repeating. In some cases, repeating those stepsinclude adjusting an energy level of ablation or a number of ablationelements for ablating tissue proximate the vessel based on the result ofassessing denervation of the vessel. The repeating with or without theadjusting until denervation of the vessel is achieved is preferablyperformed in real time. The recording and assessing are preferably donein real time so that the assessment results can be provided as feedbackto the user who can repeat the steps in real time, including adjustingthe denervation in real time if necessary, to achieve the desireddenervation for the patient undergoing the medical procedure in realtime. If it is desired to adjust the position of the ablation ordenervation elements the step of performing a baseline evoked responsemeasurement should be repeated after the elements are repositioned andbefore the subsequent denervation step.

As an example, the baseline recording of evoked responses is performedto compute a parameters Ai which can be derived from a number ofvariables such as the maximum signal amplitude or area under the firstvolley as mentioned above. The post-ablation assessment yields a secondparameter Ao. The degree of denervation is computed as the DNAi given byAo/Ai. The neural assessment method can be extended to provide closedloop control of denervation by interleaving ablation with neuralassessment, for example, by incrementing the number of electrodesinvolved in ablation after each neural assessment until the DNAi isreduced below a certain threshold or falls within a preset range. Thisapproach minimizes the need to move the catheter to different segmentsof the vessel for total coverage of denervation. Neural assessments canbe done with bipolar or unipolar stimulation, but preferably bipolar.The bipolar stimulus can be either constant current or constant voltage,and is preferably a square wave with a pulse duration of about 0.1-1millisecond, more preferably about 0.2-0.5 millisecond, and an amplitudeof about 1-20 mA or 1-20 V, more preferably about 5-10 mA or 5-10 V. Thestimulus is repeated typically at a rate of about 0.5-20 Hz for a totalof about 5-30 seconds.

An alternative to electrical stimulation is pharmacological stimulation.Examples include the use of alpha-latrotoxin or ciguatoxin, which can beapplied extraluminally (e.g., at 1 nM dose) to the renal artery. Thedrug can be delivered using a micro-infusion needle that penetrates thearterial wall to reach the perivascular axons. For instance, a ballooncan be used to drive the needle into the arterial wall. The drug cantemporarily activate or accelerate the release of neurotransmitters fromperivascular varicosities and thus generate the evoked response forsignal recording. The micro-infusion needle will replace the stimulationelectrodes of the above embodiments while the recording electrodes arestill used to record the response to the nerve stimulation produced bythe drug.

The above-described method provides a direct and immediate assessment ofthe transvascular denervation procedure. It ensures optimal titration ofenergy to achieve denervation end point and provides a way to predictclinical outcome of denervation, preferably in real time.

In the description, numerous details are set forth for purposes ofexplanation in order to provide a thorough understanding of the presentinvention. However, it will be apparent to one skilled in the art thatnot all of these specific details are required in order to practice thepresent invention. It is also noted that the invention may be describedas a process, which is usually depicted as a flowchart, a flow diagram,a structure diagram, or a block diagram. Although a flowchart maydescribe the operations as a sequential process, many of the operationscan be performed in parallel or concurrently. In addition, the order ofthe operations may be re-arranged.

From the foregoing, it will be apparent that the invention providesmethods, apparatuses and programs stored on computer readable media forablation using an irrigated catheter device with multiple segmentedablation segments. Additionally, while specific embodiments have beenillustrated and described in this specification, those of ordinary skillin the art appreciate that any arrangement that is calculated to achievethe same purpose may be substituted for the specific embodimentsdisclosed. This disclosure is intended to cover any and all adaptationsor variations of the present invention, and it is to be understood thatthe terms used in the following claims should not be construed to limitthe invention to the specific embodiments disclosed in thespecification. Rather, the scope of the invention is to be determinedentirely by the following claims, which are to be construed inaccordance with the established doctrines of claim interpretation, alongwith the full range of equivalents to which such claims are entitled.

What is claimed is:
 1. A catheter apparatus for assessing denervationcomprising: an elongated catheter body having a proximal end and adistal end and a longitudinal axis extending in a longitudinal directionbetween the distal end and the proximal end; a deployable structurecoupled to the catheter body, the deployable structure being deployableoutwardly from the longitudinal axis and contractible inwardly towardthe longitudinal axis of the catheter body, the deployable structurecomprising a deployable sleeve having a semi-compliant outer shell and anon-compliant inner shell, wherein the semi-compliant outer shell isconfigured to stretch outwardly from the longitudinal axis away from thenon-compliant inner shell in a deployed arrangement of the deployablestructure, wherein at least a portion of the catheter body is disposedinside the deployable sleeve; one or more ablation elements disposed onthe deployable sleeve to move outwardly and inwardly with the deployablesleeve, the one or more ablation elements being powered to applyablation energy to a vessel of a patient; one or more stimulationelements disposed on the deployable sleeve to move outwardly andinwardly with the deployable sleeve, the one or more stimulationelements being powered to supply nerve stimulating signals to thevessel; and one or more recording elements spaced from the one or morestimulation elements, the one or more recording elements being disposedon the deployable sleeve to move outwardly and inwardly with thedeployable sleeve and being configured to record evoked electricalresponses of the vessel in response to the nerve stimulating signals. 2.The catheter ablation apparatus of claim 1, wherein the one or morestimulation elements are proximal relative to the one or more recordingelements.
 3. The catheter apparatus of claim 1, wherein a most distalablation element of the one or more ablation elements is no more distalthan at least one of the one or more stimulation elements and a mostproximal ablation element of the one or more ablation elements is nomore proximal than at least one of the one or more recording elements.4. The catheter apparatus of claim 1, wherein at least one of the one ormore ablation elements is also a stimulation element or a recordingelement.
 5. The catheter apparatus of claim 1, wherein the one or morerecording elements are spaced from one of the one or more stimulationelements by one of a longitudinal spacing, a lateral spacing, or acombined longitudinal and lateral spacing.
 6. The catheter apparatus ofclaim 1, wherein the one or more recording elements are configured torecord the evoked electrical responses of the vessel in response to thenerve stimulating signals by direct contact with a luminal wall of thevessel.
 7. The catheter apparatus of claim 1, wherein the deployablesleeve comprises an electrically insulative material.
 8. The catheterapparatus of claim 1, wherein the portion of the catheter body disposedinside the deployable sleeve includes a plurality of holes for fluid topass therethrough to facilitate pushing the deployable sleeve radiallyoutwardly relative to the catheter body in the deployed arrangement. 9.The catheter apparatus of claim 8, further comprising: a plurality ofdraw strings extending from inside the portion of the catheter bodydisposed inside the deployable sleeve through the plurality of holes tothe deployable sleeve to draw the deployable sleeve radially inwardlyrelative to the catheter body in an undeployed arrangement.
 10. Thecatheter apparatus of claim 1, wherein the deployable structure iscontractible to a contracted arrangement and is deployable to thedeployed arrangement, and wherein the deployable structure includes ananti-occlusion feature to permit fluid flow in the vessel between aproximal end and a distal end of the deployable structure in thedeployed arrangement.
 11. A catheter apparatus for assessing denervationcomprising: an elongated catheter body having a proximal end and adistal end and a longitudinal axis extending in a longitudinal directionbetween the distal end and the proximal end, a portion of the catheterbody including a plurality of holes; a structure coupled to the catheterbody, the structure comprising a deployable sleeve, wherein at least aportion of the catheter body is disposed inside the deployable sleeve;one or more ablation elements disposed on the deployable sleeve andbeing powered to apply ablation energy to a vessel; one or morestimulation elements disposed on the deployable sleeve, the one or morestimulation elements being powered to supply nerve stimulating signalsto the vessel; one or more recording elements spaced from each other andfrom the one or more stimulation elements, the one or more recordingelements being disposed on the deployable sleeve and being configured torecord evoked electrical responses of the vessel in response to thenerve stimulating signals; and wherein the portion of the catheter bodydisposed inside the deployable sleeve is configured to facilitatedeployment of the deployable sleeve outwardly from the longitudinal axisof the catheter body to move the one or more ablation elements, the oneor more stimulation elements, and the one or more recording elementsoutwardly to a deployed arrangement, and wherein the structure comprisesa plurality of draw strings extending from inside the portion of thecatheter body disposed inside the deployable sleeve through theplurality of holes to the deployable sleeve to draw the deployablesleeve radially inwardly relative to the catheter body in an undeployedarrangement.
 12. The catheter apparatus of claim 11, wherein at leastone of the one or more ablation elements is also a stimulation elementor a recording element.
 13. The catheter apparatus of claim 11, whereina most distal ablation element of the one or more ablation elements isno more distal than at least one of the one or more stimulation elementsand a most proximal ablation element of the one or more ablationelements is no more proximal than at least one of the one or morerecording elements.
 14. The catheter apparatus of claim 11, wherein theone or more recording elements are configured to record evokedelectrical responses of the vessel in response to the nerve stimulatingsignals by direct contact with a luminal wall of the vessel.
 15. Thecatheter apparatus of claim 11, wherein the deployable sleeve comprisesan electrically insulative material.
 16. The catheter apparatus of claim11, wherein the structure is contractible to the undeployed arrangementand is deployable to the deployed arrangement, and wherein the structureincludes an anti-occlusion feature to permit fluid flow in the vesselbetween a proximal end and a distal end of the structure in the deployedarrangement.
 17. The catheter apparatus of claim 16, wherein theanti-occlusion feature comprises a plurality of rib channels connectinga lumen of the portion of the catheter disposed inside the deployablesleeve to an enclosed interior of the deployable sleeve between an outershell of the deployable sleeve and an inner shell of the deployablesleeve.
 18. The catheter apparatus of claim 17, wherein the outer shellof the deployable sleeve is semi-compliant, and wherein the inner shellof the deployable sleeve is noncompliant.